The common occurrence and serious outcome of prostate cancer skeletal lesions has prompted the National Cancer Institute Prostate Cancer Progress Review Group to state that there is a need to study prostate cancer skeletal metastasis and a need of animal models to address this disease. Unfortunately, there is a dearth of research activity in this field. In the current proposal, we attack this problem by combining experts in prostate cancer research with bone metabolism experts in four interrelated projects supported by two cores. Our ultimate goal is to define the cellular and molecular mechanisms that lead to prostate cancer skeletal metastases. The central theme of our Program is that the bone microenvironment has unique properties that foster the development of prostate cancer metastasis. These properties include a combination of factors that cause prostate cancer cells to migrate and attach to bone and enhance their ability to thrive in the bone microenvironment. To develop this theme, we will perform the following interactive projects: Project 1 will explore the role of stromal-derived factor in the bone marrow and its receptor on the prostate cancer cells that favor the cells' ability to metastasize to bone. Project 2 will develop the theme that protease-activated receptor 1 is an important mediator of prostate cancer skeletal metastasis. Project 3 will examine the mechanisms through which bone morphogenetic proteins contribute to development of osteoblastic lesions. Project 4 will explore the role of parathyroid hormone-related protein on the development of osteoblastic lesions at the metastatic site. These projects will be tied together through use of several animal models including SCID-human and ossicle development in vivo. The animal model and animal-related services will be supported by the Animal Core (Core A) in an efficient and cost-effective manner. Bone evaluation, including histomorphometry, densitometry and radiographic imaging will be supported by a Bone Core (Core B).